Despite considerable global efforts with oral iron supplementation and fortification, iron deficiency remains the most common and widespread nutritional disorder in the world. A key reason for this failure is that, to address iron deficiency, oral iron supplementation needs to be well tolerated, cheap, safe and effective. However, currently available preparations fail in at least one of these criteria. Simple ferrous iron [Fe(II)] salts are most commonly used as these are inexpensive and the iron is well absorbed. However, these are poorly tolerated and indeed appear to enhance systemic infection rates, may induce undesirable changes to commensal bacteria of the colon and increase pro-inflammatory signalling of the gut epithelium. Some forms of ferric iron [Fe(III)] (e.g. ferric pyrophosphate) are considered safer and better tolerated in the gut lumen than Fe(II), but have the disadvantage that they are poorly absorbed.
As examples of prior art iron supplements, WO 2005/094203 (Navinta) and WO 2005/000210 (Chromaceutical) relate to processes for making sodium ferric gluconate complexes (Ferrlecit™) for use as an intravenously administered iron supplements. These high molecular weight iron saccharidic complexes are formed when the surface of freshly precipitated iron hydroxide particles are coated with gluconate molecules, and subsequently form agglomerated mixtures of secondary complexes. US 2005/0256328 (Justus & Hanseler) also describe similar ferric gluconate complexes for intravenous delivery. WO 2004/07444 and US 2008/0274210 (Globoasia LLC) describe phosphate binding materials based on stoichiometric ferric citrate coordination complexes.
WO 2008/096130 (Medical Research Council) describes ferric iron oxo-hydroxide colloids that are modified synthetically so that dietary carboxylic acid ligands are non-stoichiometrically incorporated into the iron oxo-hydroxide structure. These colloidal ligand modified iron oxo-hydroxides, in which the mineral phase is disrupted, mimic the ferritin core—a natural dietary source of iron—and thus are well absorbed in humans with few or no side effects, providing a safe and efficacious oral iron supplement. The ligand modified ferric oxo-hydroxides described in WO 2008/096130 include nanoparticles of iron hydroxide modified with adipate (A) and tartrate (T) carboxylate ligands in a 1:1:2 T:A:Fe molar ratio (Iron Hydroxide Adipate Tartrate or “IHAT”, see http://www.rsc.org/chemistryworld/2014/12/solving-iron-solubility-problem-profile-mrc). These materials are shown to be alternative safe iron delivery agents and their absorption in humans correlated with serum iron increase (P<0.0001) and direct in vitro cellular uptake (P=0.001), but not with gastric solubility. IHAT also showed ˜80% relative bioavailability to Fe(II) sulfate in humans and, in a rodent model, IHAT was equivalent to Fe(II) sulfate at repleting haemoglobin. Furthermore, IHAT did not accumulate in the intestinal mucosa and, unlike Fe(II) sulfate, promoted a beneficial microbiota. In cellular models, IHAT was 14-fold less toxic than Fe(II) sulfate/ascorbate, itself has minimal acute intestinal toxicity in cellular and murine models and shows efficacy at treating iron deficiency anaemia (Pereira et al., Nanoparticulate iron(III) oxo-hydroxide delivers safe iron that is well absorbed and utilised in humans, Nanomedicine, 10(8): 1877-1886, 2014). Other papers describing IHAT and its uses for treating iron deficiency include Aslam, et al., Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice (FASEB J. 28(8):3671-8, 2014) and Powell et al., A nano-disperse ferritin-core mimetic that efficiently corrects anaemia without luminal iron redox activity (Nanomedicine. 10(7):1529-38, 2014).
IHAT materials are produced in WO 2008/096130 by co-precipitating ferric iron ions and the organic acids by raising the pH of an aqueous solution of the components from a pH at which they are soluble to a higher pH at which polymeric ligand modified ferric oxo-hydroxide forms. The precipitate is then dried, either by oven drying at 45° C. for 4-14 days or freeze-drying at −20° C. and 0.4 mbar for a longer period, thereby producing ligand modified ferric oxo-hydroxide suitable for formulation as an iron supplement. However, the success of IHAT as a widely used supplement means that there is a need in the art to improve the methods used for the production of these materials, such that the materials are produced cheaply at scale.